Compound 16 interaction with 20s B5 sub-unit

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The proteasome's role in intracellular degradation spans multiple pathways, encompassing signaling, apoptosis, and inflammatory responses. A diverse array of synthetic and natural inhibitors can bind to the beta 5 sub-unit, exhibiting chymotrypsin-like mechanisms; however, their "warhead" structures often lack specificity, are highly reactive, and exhibit instability. Compound 16, demonstrated here in non-covalent interaction with the B5 subunit of a beta ring, is a novel compound engineered through sequential optimization of S-homo-phenylalanine to target chymotrypsin-like mechanisms. Compound 16 forms an optimal interaction at the S3 binding pocket accompanied by weaker S1 binding pocket and sub-pocket interactions. This compound displays higher affinity for B5 (Ki=1.2nM) compared to the covalent inhibitor Bortezomib (Ki=0.56nM). By exclusively inhibiting the B5 subunit, it is capable of halting cancer cell proliferation.